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Aberrant expression of miR‐218 and miR‐204 in human mesial temporal lobe epilepsy and hippocampal sclerosis—Convergence on axonal guidance
Author(s) -
Kaalund Sanne S.,
Venø Morten T.,
Bak Mads,
Møller Rikke S.,
Laursen Henning,
Madsen Flemming,
Broholm Helle,
Quistorff Bjørn,
Uldall Peter,
Tommerup Niels,
Kauppinen Sakari,
Sabers Anne,
Fluiter Kees,
Møller Lisbeth B.,
Nossent Anne Y.,
Silahtaroglu Asli,
Kjems Jørgen,
Aronica Eleonora,
Tümer Zeynep
Publication year - 2014
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.12839
Subject(s) - hippocampal formation , epilepsy , hippocampal sclerosis , hippocampus , microrna , rna , biology , neuroscience , temporal lobe , gene expression , in situ hybridization , human brain , gene , genetics
Summary Objective Mesial temporal lobe epilepsy ( MTLE ) is one of the most common types of the intractable epilepsies and is most often associated with hippocampal sclerosis ( HS ), which is characterized by pronounced loss of hippocampal pyramidal neurons. micro RNA s (mi RNA s) have been shown to be dysregulated in epilepsy and neurodegenerative diseases, and we hypothesized that mi RNA s could be involved in the pathogenesis of MTLE and HS . Methods mi RNA expression was quantified in hippocampal specimens from human patients using mi RNA microarray and quantitative real‐time polymerase chain reaction RT ‐ PCR , and by RNA ‐seq on fetal brain specimens from domestic pigs. In situ hybridization was used to show the spatial distribution of mi RNA s in the human hippocampus. The potential effect of mi RNA s on targets genes was investigated using the dual luciferase reporter gene assay. Results mi RNA expression profiling showed that 25 mi RNA s were up‐regulated and 5 were down‐regulated in hippocampus biopsies of MTLE / HS patients compared to controls. We showed that miR‐204 and miR‐218 were significantly down‐regulated in MTLE and HS , and both were expressed in neurons in all subfields of normal hippocampus. Moreover, miR‐204 and miR‐218 showed strong changes in expression during fetal development of the hippocampus in pigs, and we identified four target genes, involved in axonal guidance and synaptic plasticity, ROBO 1, GRM 1, SLC 1A2, and GNAI 2, as bona fide targets of miR‐218. GRM 1 was also shown to be a direct target of miR‐204. Significance miR‐204 and miR‐218 are developmentally regulated in the hippocampus and may contribute to the molecular mechanisms underlying the pathogenesis of MTLE and HS .